Reflectance confocal microscopy, a type of scanning laser microscopy, has shown early success for non- invasive screening and diagnosis of skin malignancies while reducing unnecessary biopsy of benign lesions, guiding surgery by detection of cancer margins without the need for biopsies, and by monitoring patients post-treatment without requiring further biopsies. Because the technique is non-invasive and immediate, the clinician can look at as many features as necessary to arrive at a diagnosis. This is contrasted with current practice, in which the clinician must guess at the best one or two locations for a painful, potentially disfiguring biopsy, and then wait several days for a definitive diagnosis froma pathologist. Care is improved and substantial cost savings accrue, because many unnecessary biopsies can be avoided (for skin cancer, as many as 80% of all biopsies show normal or benign tissue, at a cost of some $5 billion annually in the US). Cancer of organs other than skin can be similarly diagnosed. For example, initial success is being seen using this technology for the detection of oral cancer. However, large instrument size remains a barrier toward widespread use of this technique in any but the most accessible sites on the body. To translate the diagnostic potential of confocal reflectance microscopy to other locations in the body, we are developing a new instrument called the integrated scanning laser microscope, or iLSM, that will be small enough for use in a pencil probe or endoscope. This instrument will achieve high resolution, high contrast images showing cellular detail, and, significantly, simultaneously provide a wide-field color video image of the tissue surface, allowing the clinician see where the microscopic images are being taken in the context of the surface features of a lesion. This wide-field view is essential for accurate sampling of a suspicious lesion, and has been missing from all previous attempts to miniaturize scanning laser microscopes. Recent technological advances in two areas, MEMS active optics and miniaturized CMOS cameras, have made the iLSM possible. This project takes a novel approach to integrate a custom MEMS 3D laser scanner into a centimeter-scale, high NA objective lens. Microscopy sections can be en face, oblique, vertical, or fully 3D, with a field of view of 300 ?m. The microscope uses an annular pupil that devotes the outer 75% of the aperture area to high NA imaging, ensuring high resolution and efficient collection of scattered light. The inner 25% of the aperture area is reserved for a separate low NA, wide-field camera, also integrated into the lens, that will show several millimeters of tissue. This project will develop the custom laser scanner and validate the approach with in vivo imaging of the skin of 30 volunteers.